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United States Patent |
5,292,918
|
Gosteli
,   et al.
|
March 8, 1994
|
Diastereoselective process for preparing n-substituted amino acids and
derivatives
Abstract
A process for preparing an (S,S) or (R,R) diastereoisomer of the formula:
##STR1##
or salts, esters or amides thereof, wherein R.sup.3 and R.sup.4
independently represent hydrogen, alkyl, aryl or aryl substituted with
halogen, alkyl, nitro or alkoxy, and n and m independently represent
integers from one to six, comprising combining a cyanide compound of the
formula:
M.sup.1 C.tbd.N (III)
wherein M.sup.1 is hydrogen, trimethylsilyl or a metal, with an optional
proton source, a solvent and a Lewis acid of the formula:
M.sup.2 X.sub.4, AlCl.sub.3 or BF.sub.3 (IV)
wherein M.sup.2 is Sn or Ti and X represents chloro, bromo, fluoro or iodo,
with an .alpha.-amino acid compound or salts or esters thereof, followed
by addition of an acyl or acetal compound to give the diastereoisomer of
formula (X).
Inventors:
|
Gosteli; Jacques (Basel, CH);
Mergelsberg; Ingrid (Dagmersellen, CH);
Tanner; Markus (Schachen, CH)
|
Assignee:
|
Schering Corporation (Kenilworth, NJ)
|
Appl. No.:
|
934537 |
Filed:
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October 6, 1992 |
PCT Filed:
|
March 29, 1991
|
PCT NO:
|
PCT/US91/02034
|
371 Date:
|
October 6, 1992
|
102(e) Date:
|
October 6, 1992
|
PCT PUB.NO.:
|
WO91/17141 |
PCT PUB. Date:
|
November 14, 1991 |
Current U.S. Class: |
558/352; 558/348; 558/350; 558/351; 558/390; 558/441 |
Intern'l Class: |
C07C 253/30 |
Field of Search: |
558/332,346,350,351,352
|
References Cited
U.S. Patent Documents
4551537 | Nov., 1985 | Mai et al. | 546/330.
|
4652668 | Mar., 1987 | Kim | 558/390.
|
Foreign Patent Documents |
0336368 | Oct., 1989 | EP.
| |
3624376 | Jan., 1988 | DE.
| |
62-20486 | Aug., 1987 | JP.
| |
Other References
P. K. Subramanian and R. W. Woodward, Synth. Commun. 16(3), pp. 337-342
(1986).
K. Weinges, G. Graab, D. Nagel and B. Stemmle, Chem. Ber. vol. 104 pp.
3594-3606 (1971).
K. Weinges, K. Gries, B. Stemmle, W. Schrank, Chem., Ber. vol. 110 pp.
2098-2105 (1977).
K. Weinges and B. Stemmle, Chem. Ber. vol. 106, pp. 2291-2297 (1973).
K. Kawashiro, S. Morimoto and H. Yoshida, Bull. Chem., Soc. Jpn, 58(7), pp.
1903-1912 (1985).
C.A. 111: 114878h, Inoue, et al., (1989), vol. 111.
|
Primary Examiner: Brust; Joseph P.
Attorney, Agent or Firm: Majka; Joseph T., Mazer; Edward H., Gould; James M.
Parent Case Text
The present application is the U.S. national application corresponding to
International Application No. PCT/US91/02034, filed Mar. 29, 1991 and
designating the United States, which PCT application is in turn a
continuation-in-part of U.S. application Ser. No. 07/514,798, filed Apr.
26, 1990, now abandoned, the benefit of which applications is claimed
pursuant to the provisions of 35 U.S.C. .sctn..sctn.120, 363 and 365(C).
Claims
We claim:
1. A process for preparing an (S,S) or (R,R) diastereoisomer of the
formula:
##STR7##
or salts, esters or amides thereof, wherein R.sup.3 and R.sup.4
independently represent hydrogen, alkyl, aryl or aryl substituted with
halogen, alkyl, nitro or alkoxy, and n and m independently represent
integers from one to six, comprising combining a cyanide compound of the
formula:
M.sup.1 C.tbd.N (III)
wherein M.sup.1 is hydrogen, trimethylsilyl or a metal selected from the
group consisting of sodium, potassium, lithium, cesium, iron, nickel,
cadmium and zinc, with an optionally added proton source, a solvent and a
Lewis acid of the formula:
M.sup.2 X.sub.4, AlCl.sub.3 or BF.sub.3 (IV)
wherein M.sup.2 is Sn or Ti and X represents chloro, bromo, fluoro or iodo,
with an optically active .alpha.-amino acid compound of formula (I):
##STR8##
or salts, esters or amides thereof, wherein R.sup.3 and m are as defined
hereinbefore, followed by addition of an acyl or acetal compound of
formula (II):
##STR9##
wherein m, n and R.sup.4 are as defined hereinbefore, R.sup.1 is hydrogen,
alkyl or phenyl and R.sup.2 and R.sup.3 independently represent alkyl.
2. The process of claim 1 wherein the optically active diastereomer (X) is
recovered from the reaction mixture.
3. The process of claim 1 wherein diastereoisomer (X), R.sup.3 and R.sup.4
are hydrogen.
4. The process of claim 1 wherein diastereoisomer (X) is the (S,S)
diastereoisomer.
5. The process of claim 1 wherein the cyanide compound (III) is sodium
cyanide.
6. The process of claim 1 wherein the solvent is a C-1 to C-10 monohydric
alcohol.
7. The process of claim 1 wherein the solvent is methanol.
8. The process of claim 1 wherein a drying agent is employed during the
process.
9. The process of claim 1 wherein the process is carried out at a
temperature in the range from about -100.degree. to about 0.degree. C.
10. The process of claim 1 wherein the process is carried out at a
temperature in the range from about -60.degree. C. to about -20.degree. C.
11. The process of claim 1 wherein the process is carried out at a
temperature in the range from about -60.degree. C. to about -40.degree. C.
12. The process of claim 1 wherein the process is carried out using from
about 5 moles to about equimolar amounts of acyl or acetal compound (II),
from about 10 moles to about equimolar amounts of compound (III), from
about 10 moles to about equimolar amounts of compound (IV) and about one
mole .alpha.-amino acid compound (I).
13. The process of claim 1 wherein the process is carried out by adding a
proton source to the reaction mixture.
14. The process of claim 13 wherein the added proton source is a mineral or
organic acid.
15. The process of claim 1 wherein the Lewis acid is of the formula M.sup.2
X.sub.4 (IV) wherein M.sup.2 and X are as defined hereinbefore.
16. The process of claim 1 wherein the Lewis acid is SnCl.sub.4.
Description
BACKGROUND
Diastereoisomeric amino acids and derivatives are useful intermediates for
preparing various pharmaceutical compounds such as enkephalinase
inhibitors which are useful for treating pain or as inhibitors of the
angiotensin converting enzyme (ACE) which are useful for treating
hypertension or reducing elevated intraocular pressure associated with
glaucoma. U.S. Pat. No. 4,652,668 discloses a process for preparing a
class of pharmaceuticals useful in inhibiting angiotensin converting
enzyme in humans such as N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-proline
maleate salt is representative. German Offenlegungsschrift DE 3624376 A1
discloses a process for preparing 0-Acyl-glycosyl amines derivatives
useful for preparing amino acids and derivatives by first treating an
aldehyde compound with 0-acyl glycosyl amine under acidic conditions,
followed by treatment with trimethylsilyl or sodium cyanide and tin or
zinc (tetra)-chloride in tetrahydrofuran, isopropanol or chloroform. P. K.
Subramanian and R. W. Woodward, Synth. Commun. 16 (3), pp. 337-342 (1986)
disclose a four-step asymmetric Strecker synthesis for preparing
(R)-(+)-2-methyl-3-phenylalanine by utilizing (S) phenylalanine as the
chiral auxiliary reagent. K. Weinges, G. Graab, D. Nagel and B. Stemmle,
Chem. Ber. Vol. 104 , pp. 3594-3606 (1971) disclose an external asymmetric
Strecker synthesis of .alpha.-methyl-amino acids. K. Weinges, K. Gries, B.
Stemmle, W. Schrank, Chem. Ber. Vol. 110, pp. 2098-2105 (1977) disclose an
asymmetric Strecker synthesis with (S)-(-)-1-phenylethylamine as a chiral
handle to afford stereochemically homogeneous
.alpha.-methyl-.alpha.-aminonitriles. K. Weinges and B. Stemmle, Chem.
Ber. Vol. 106, pp. 2291-2297 (1973) disclose an asymmetric Strecker
synthesis of aliphatic .alpha.-methyl-.alpha.-amino acids. S. Inoue et al.
J. Chem. Soc. Chem. Comm. 1981, pp. 229. Japan Kokai Tokkyo Koho, JP
01047754 A2 Feb. 22, 1989 Heisei, JP 87-204860 Aug. 18, 1987,
CA111(13):114878h discloses a process for preparing
.gamma.-1-carboxyethylamino-.gamma.-phenylbutyronitrile and
.gamma.-phenylbutyric acid derivatives as intermediates for
anti-hypertensive compounds. The article of K. Kawashiro, S. Morimoto and
H. Yoshida, Gas chromatography-mass spectrometry of trimethylsilylated
imino derivatives of alanine, Bull. Chem. Soc. Jpn., 58(7), pp. 1903-12
discloses trimethylsilylation of seven imino derivatives of alanine with
N,O-bis(trimethylsilyl)trifluoracetamide in acetonitrile. It would be
desirable to provide a process for preparing either (S,S) or (R,R)
diastereoisomers in high optical yields which is relatively inexpensive
and which does not require a protecting group for the amine starting
material.
SUMMARY OF THE INVENTION
The present invention is directed to a process for preparing an (S,S) or
(R,R) diastereoisomer of the formula:
##STR2##
or salts, esters or amides thereof, wherein R.sup.3 and R.sup.4
independently represent hydrogen, alkyl, aryl or aryl substituted with
halogen, alkyl, nitro or alkoxy, and n and m independently represent
integers from one to six, comprising combining a cyanide compound of the
formula:
M.sup.1 C.tbd.N (III)
wherein M.sup.1 is hydrogen, trimethylsilyl or a metal, with an optionally
added proton source, a solvent and a Lewis acid of the formula:
M.sup.2 X.sub.4, AlCl.sub.3 or BF.sub.3 (IV)
wherein M.sup.2 is Sn or Ti and X represents chloro, bromo, fluoro or iodo,
with an optically active .alpha.-amino acid compound of formula (I):
##STR3##
or salts, esters or amides thereof, wherein R.sup.3 and m are as defined
hereinbefore, followed by addition of an acyl or acetal compound of the
formula (II):
##STR4##
wherein m, n and R.sup.4 are as defined hereinbefore, R.sup.1 is hydrogen,
alkyl or phenyl and R.sup.2 and R.sup.3 independently represent alkyl or
cycloalkyl, to give the diastereoisomer of formula (X).
The present invention has the advantage of preparing diastereoisomers of
formula (X). That is, either the (S,S) or the (R,R) diastereoisomer can be
prepared by selection of the desired optically active .alpha.-amino acid
(I) beforehand. The present process advantageously uses as few or fewer
steps than other processes previously taught. The present process has the
further advantage of utilizing relatively inexpensive starting materials
or reagents that are commonly available compared with other known
processes, thereby reducing the overall cost of the process. Another
advantage is that the present process can employ unprotected primary
.alpha.-amino acids, and thus eliminates the additional costs and steps
associated with such use of protecting groups as described in DE 3624376,
supra. The present process also provides higher yields because more
starting material is converted to the desired diastereoisomer rather than
forming a racemic mixture.
DETAILED DESCRIPTION OF THE INVENTION
The term "diastereoisomer" generally refers to any group of four optical
isomers occurring in compounds containing two asymmetric carbon atoms or
two optically active centers, as defined in Gessner G. Hawley(ed.), The
Condensed Chemical Dictionary, 10th Edition, Van Nostrand Reinhold Company
Inc., New York, 1981, 1135 pp., whose teachings are incorporated herein by
reference.
The stereospecificity of the diastereoisomer (X) can be determined
beforehand by the appropriate selection of the .alpha.-amino acid compound
(I), the nature of the metal cyanide and the Lewis Acid. For example, if
one uses the .alpha.-amino acid compound (I) which is predominantly the
optically active S enantiomer, the present process will yield the
diastereoisomer (X) which possesses predominantly the (S,S)
diastereoisomer. Similarly, if one uses the .alpha.-amino acid compound
(I) which is predominantly the optically active R enantiomer, the present
process will yield the (R,R) diastereoisomer. The stereochemistry of the
diastereoisomer compounds (X) is referenced with regard to the two
optically active centers for this compound:
##STR5##
The term "alkyl" (including the alkyl portions of alkoxy)--represents a
straight or branched, saturated hydrocarbon chain preferably having from 1
to 6 carbon atoms, such as methyl, ethyl, isopropyl, n-propyl, n-butyl,
t-butyl, pentyl, hexyl and the like.
The term "aryl" represents a carbocyclic group having from 6 to 14 carbon
atoms and having at least one fused benzenoid ring, with all available
substitutable carbon atoms of the carbocyclic group being intended as
possible points of attachment. Preferred aryl groups are phenyl,
1-naphthyl, 2-naphthyl and indanyl. The term "substituted aryl" refers to
said carbocyclic group being optionally substituted with 1 to 3 moieties
independently selected from halo, alkyl, alkoxy or nitro. Representative
substituted aryl groups include methylphenyl, chlorophenyl,
1-methylnapthyl and the like.
Cyanide compounds of the formula M.sup.1 C.tbd.N (III) wherein M.sup.1 is
hydrogen, trimethylsilyl or a metal which can be sodium, potassium,
lithium, cesium, iron, nickel, cadmium and zinc are well-known compounds.
Suitable cyanide reagents include hydrogen cyanide (HCN), trimethylsilyl
cyanide (CNSi(CH.sub.3).sub.3), iron dicyanide (Fe(CN).sub.2), cadmium
dicyanide (Cd(CN).sub.2), zinc dicyanide (Zn(CN).sub.2), sodium cyanide
(NaCN), lithium cyanide (LiCN), cesium cyanide (CsCN) and potassium
cyanide (KCN), preferably sodium cyanide and potassium cyanide.
The Lewis acid compounds of formula (IV) are well-known compounds as
defined in J. March, Advanced Organic Chemistry, Reactions, Mechanisms,
and Structure, 3rd Edition, John Wiley & Sons. New York, (1985) 1346
pages. Such Lewis Acids include aluminium trichloride (Al(Cl.sub.3)) and
boron trifluoride (BF.sub.3). Preferably, M is Sn and X in the formula
M.sup.2 X.sub.4 is chloro, otherwise known as tin tetrachloride.
The acyl or acetal compounds of formula (II) are known, such as described
in Houben Weyl, Methoden der Organischen Chemie, Band 7, Georg Thieme
Verlag Stuttgart, 1954. Also preferred is that R.sup.1 of acyl compound
(IIa) is hydrogen. The most preferred compound of formula (IIa) is
phenylacetaldehyde. Alternatively, R.sup.1 can be alkyl or phenyl. An
acetal of formula (IIb) can also be employed in place of acyl (IIa),
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n are as defined
hereinbefore. Mixtures of acyl (IIa) and acetal (IIb) can also be
employed.
The .alpha.-amino acid compounds (I) are also well known, as described in
E. P. Greenstein, Chemistry of the Amino Acids, RE Krieger Publishing Co.,
Malabar, Fla. 1984, Vol. 1-3.
The salt forms of diastereoisomer (X) or .alpha.-amino acid (I) can be
prepared by contacting the free base form with a sufficient amount of the
desired acid to produce a salt in the conventional manner. The free base
forms may be regenerated by treating the salt with a suitable dilute
aqueous base solution such as dilute aqueous sodium hydroxide, potassium
carbonate, ammonia or sodium bicarbonate. Examples of suitable acids for
such salt formation are hydrochloric, sulfuric, phosphoric, acetic,
citric, oxalic, malonic, salicylic, malic, fumaric and other mineral and
carboxylic acids known to those skilled in the art.
The esters or amides of diastereoisomer (X) or .alpha.-amino acid (I) can
be prepared by conventional procedures such as described in J. March,
supra or in Tetrahedron Letters Vol. 36, pp. 2409 (1980).
The acyl or acetal compounds of formula (II) can be contacted with the
.alpha.-amino acid compound of formula (I) in amounts effective to give
the desired diastereoisomers of formula (X). Such amounts can range from
excess to about 0.5: 1 (moles acyl compound (II): mole of .alpha.-amino
acid compound (I)), more preferably from about 5 moles to about equimolar
amounts of acyl compound (II), most preferably from about 1.7 to about
equimolar amounts of acyl compound (II).
The cyanide compound of formula (III) can be contacted with the
.alpha.-amino acid compound of formula (I) in amounts ranging from excess
to about 0.1 moles cyanide compound (III): mole of compound (I), more
preferably from about 10 moles to about equimolar amounts of cyanide
compound (III), most preferably about equimolar amounts of cyanide
compound (III).
The Lewis Acid of formula (IV) can be contacted with the .alpha.-amino acid
compound of formula (I) in amounts ranging from a molar excess to about
equimolar amounts of the Lewis Acid compound (IV): mole .alpha.-amino acid
compound (I). More preferably, from about 10 moles to about equimolar
amounts of halogenated compound (IV), are reacted. Most preferably from
about 3 to about 1.1 moles halogenated compound (IV) are reacted.
The solvent employed in the present invention can be from a broad class of
polar solvents capable of dissolving or suspending the reactants.
Representative solvents include, but are not limited to C-1 to C-10
monohydric alcohols (one OH group), such as methanol, ethanol, n-propanol,
iso-propanol, n-butanol, iso-butanol, t-butanol, n-pentanol, n-hexanol;
dihydric alcohols (two OH groups -diols) such as C-2 to C-10 derivatives
including ethylene glycol, propylene glycol, 1,2-butanediol,
1,4-butanediol, pentanediols and the like; or polyhydric alcohols (three
OH groups -triols) such as glycerol (1,2,3-propanetriol),
1,2,4-butanetriol, penta-erythritol and the like; alkyl nitriles of the
formula R-C.tbd.N wherein R is alkyl of one to ten carbon atoms such as
acetonitrile wherein R is methyl; tetrahydrofuran; glycol ethers such
ethylene glycol monoethyl ether and propylene glycol monoethyl ether; the
chlorinated hydrocarbons such as methylene dichloride, carbon
tetrachloride or chloroform; or mixtures of any of the above.
The proton source employed in the present invention can be derived from the
reactants themselves, from an optionally added acidic reagent or from any
combination thereof. For example the proton source can be derived from the
cyanide compound or reactant (III) where hydrogen cyanide is employed or
from the .alpha.-amino acid reactant (I) in reactions where the salt form
of the .alpha.-amino acid is employed, such as the hydrochloride (HCl)
salt or para-toluenesulfonic acid salt. Other acid salt forms include the
formates, acetates or sulfates. Where the proton source is derived from
the reactants, either less additional acidic reagent can be employed or no
additional acidic reagent may be needed. In situations where the proton
source is derived from an optionally added acidic reagent, any suitable
mineral or organic acid can be employed. Suitable mineral acids include
hydrochloric, sulfuric, sulfonic or phosphoric acids. Suitable organic
acids include the C-1 to C-10 alkanoic acids such as formic, acetic,
propanoic acids and the like. The additional acidic reagent can be
employed in amounts ranging from excess to about 0.5 moles acid: mole
.alpha.-amino acid (I), more preferably from about 50 to about equimolar,
most preferably about equimolar amounts.
The order of addition of the reactants generally is not critical, except
that the acyl or acetal compound (II) should be added to the reaction
mixture following mixing of the .alpha.-amino acid compound (I), cyanide
compound (III), Lewis Acid (IV) and solvent, due to the labile nature of
the acyl compound (IIa). Preferably, the acyl or acetal (II) is distilled
from any solvents, i.e. diethyl phthalate, prior to addition to the
reaction mixture. Alternatively, the acyl or acetal compound (II) can be
mixed with a suitable solvent as described hereinbefore, before addition
to the reaction mixture.
Optionally and preferably, the process is carried out under substantially
anhydrous conditions, such those provided by the use of dry reagents and
dry reaction vessels. The reactants can also be contacted in the presence
of drying agents such as molecular sieves, silica gel, sodium sulfate
(Na.sub.2 SO.sub.4) or magnesium sulfate (MgSO.sub.4). In addition,
anhydrous conditions can be supplemented by a blanket of an inert gas,
such as nitrogen, argon, helium or mixtures thereof.
The present process can be carried out at temperatures effective to give
the desired diastereoisomer (X). The process can be conducted at
temperatures ranging from about -100.degree. C. to about 0.degree. C.,
more preferably from about -60.degree. to about -20.degree. C., most
preferably from about -60.degree. C. to about -40.degree. C. The lower
temperatures are employed to minimize side reactions of the .alpha.-amino
acid compound (I), the acyl or acetal compound (II) and the Lewis Acid
(IV). Once the acyl or acetal (II) has been added to the reaction mixture,
higher temperatures can be employed, such as those ranging from about
-60.degree. C. to about 50.degree. C. The process can also be carried out
at ambient pressures, with stirring, for a time effective to give the
desired completion of the reaction.
Following completion of the reaction, the desired diastereoisomer (X) can
be recovered from the reaction mixture by conventional procedures, such as
evaporation of any solvents present, filtration, crystallization,
chromatography, distillation and the like. Generally, the reaction mixture
is filtered to remove any solids i.e. drying agents, diluted with a
suitable solvent such as methylene chloride, toluene, diethylether, ethyl
acetate and the like, washed with water, treated with a suitable base to
adjust the pH to between about 4 to about 7, preferably about 6, to
precipitate any tin salts and refiltered. The organic phase containing the
diastereoisomer (X) is separated from the aqueous phase and the solvent is
removed by distillation or crystallization to give the desired
diastereoisomer (X). Alternatively, the diastereomer need not be
recovered. For example, the reaction mixture containing the
diastereoisomer (X) can contacted with a solvent and acidic reagent such
as methanol and hydrochloric acid in order to form the amide (i.e.
--CONH.sub.2) from the cyano moiety (--C.tbd.N).
The desired diastereoisomer (X), thus prepared can be further purified by
appropriate stereochemical resolution using conventional procedures, such
as crystallization as described in Paul Newman, Optical Resolution
Procedures for Chemical Compounds, A publication of the Optical Resolution
Information Center, Manhattan College, Riverdale, N.Y. 10471, Volumes 1,
2, 3 and 4 (1984), whose preparative teachings are incorporated herein by
reference.
EXAMPLE 1
(S)-N-(1-cyano-2-phenylethyl)-S-phenylalanine hydrochloride
##STR6##
In a four-necked round bottomed flask container, 33.0 g of pulverized
molecular sieves (5 Angstom (.ANG.)) and 17.0 g of silica gel are
suspended in 167 ml of dry methanol. The mixture is cooled to a
temperature of -60.degree. C. and 11.7 ml (0.1 mole) of SnCl.sub.4 are
added. After the addition of 4.91 g (0.1 moles) NaCN and 20.2 g (0.1 mole)
of S-phenylalanine hydrochloride, 20.0 g (0.17 mole) phenacetaldehyde are
added dropwise at -60.degree. C. After one hour of stirring at -60.degree.
C. the reaction mixture is allowed to come to room temperature and is
stirred for an additional 24 hours. After removal of the molecular sieves
and silica gel, the reaction mixture is diluted with 80 ml methylene
chloride (CH.sub.2 Cl.sub.2) and 300 ml water. The pH of the reaction
mixture is adjusted to 6.0 with about 20 ml of aqueous concentrated
ammonia (NH.sub.3). The solids are removed and the organic layer is washed
with three 60 ml water portions and dried over sodium sulfate. Removal of
the solvent gives 22.9 g of the title compound, a yellow oil (yield
77.8%). The compound has a diastereomer ratio of 93% (S,S) and 7% (S,R).
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